Polo-like kinase 1 (Plk1) plays an important role in cell-cycle regulation. Recent work has suggested that Plk1 could be a bio-marker of gemcitabine response in pancreatic ductal adenocarcinoma (PDAC). Although targeting Plk1 to treat PDAC has been attempted in clinical trials, the results were not promising, and the mechanisms of resistance to Plk1 inhibition is poorly understood. In addition, the role of Plk1 in PDAC progression requires further elucidation. Here, we showed that Plk1 was associated with poor outcomes in patients with PDAC. In an inducible transgenic mouse line with specific expression of Plk1 in the pancreas, Plk1 overexpression significantly inhibited caerulein-induced acute pancreatitis and delayed development of acinar-to-ductal metaplasia and pancreatic intraepithelial neoplasia. Bioinformatics analyses identified the regulatory networks in which Plk1 is involved in PDAC disease progression, including multiple inflammation-related pathways. Unexpectedly, inhibition or depletion of Plk1 resulted in upregulation of PD-L1 via activation of the NF-kB pathway. Mechanistically, Plk1-mediated phosphorylation of RB at S758 inhibited the translocation of NF-kB to nucleus, inactivating the pathway. Inhibition of Plk1 sensitized PDAC to immune checkpoint blockade therapy through activation of an antitumor immune response.Together,Plk1 suppresses PDAC progression and inhibits NF-kB activity, and targeting Plk1 can potentiate the efficacy of immunotherapy in PDAC.
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|Published - Oct 1 2022
Bibliographical noteFunding Information:
This research was supported by NIH R01 CA157429 (to X. Liu), NIH R01 CA264652 (to X. Liu), NIH R01 CA256893 (to X. Liu), and NIH R01 CA196634 (to X. Liu). This research was also supported by the Biospecimen Procurement & Translational Pathology, Biostatistics and Bioinformatics, Flow Cytometry and Immune Monitoring Shared Resources of the University of Kentucky Markey Cancer Center (P30CA177558). The authors deeply appreciate the editing service provided by Eleanor Erikson.
©2022 American Association for Cancer Research.
ASJC Scopus subject areas
- Cancer Research